Effective termination of atrial fibrillation by SK channel inhibition is associated with a sudden organization of fibrillatory conduction.

AIMS: Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145. METHODS AND RESULTS: Eight goats were implanted with pericardial electrodes for induction of AF (30 days). In an open-chest study, the atrial conduction velocity (CV) and effective refractory period (ERP) were measured during pacing. High-density mapping of both atrial free-walls was performed during AF and conduction properties were assessed. All measurements were performed at baseline and during AP14145 infusion [10 mg/kg/h (n = 1) or 20 mg/kg/h (n = 6)]. At an infusion rate of 20 mg/kg/h, AF terminated in five of six goats. AP14145 profoundly increased ERP and reduced CV during pacing. AP14145 increased spatiotemporal instability of conduction at short pacing cycle lengths. Atrial fibrillation cycle length and pathlength (AF cycle length × CV) underwent a strong dose-dependent prolongation. Conduction velocity during AF remained unchanged and conduction patterns remained complex until the last seconds before AF termination, during which a sudden and profound organization of fibrillatory conduction occurred. CONCLUSION: AP14145 provided a successful therapy for termination of persistent AF in goats. During AF, AP14145 caused an ERP and AF cycle length prolongation. AP14145 slowed CV during fast pacing but did not lead to a further decrease during AF. Termination of AF was preceded by an abrupt organization of AF with a decline in the number of fibrillation waves.

Inhibition of Small-Conductance Calcium-Activated Potassium Current (I K,Ca) Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation.

BACKGROUND: Small-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current-and thereby the efficacy of small-conductance Ca2+-activated K+ current (I K,Ca) inhibition-might be negatively related to AF duration and the extent of AF-induced remodeling. EXPERIMENTAL APPROACH AND METHODS: To address the hypothesis of the efficacy of I K,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the I K,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring. RESULTS: I K,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved. CONCLUSIONS: Intra-atrial heterogeneity in response to I K,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, I K,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats.

Aims: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF. Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed. Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.

Stationary Atrial Fibrillation Properties in the Goat Do Not Entail Stable or Recurrent Conduction Patterns.

Introduction: Electro-anatomical mapping of the atria is used to identify the substrate of atrial fibrillation (AF). Targeting this substrate by ablation in addition to pulmonary vein ablation did not consistently improve outcome in clinical trials. Generally, the assessment of the substrate is based on short recordings (≤10 s, often even shorter). Thus, targeting the AF substrate assumes spatiotemporal stationarity but little is known about the variability of electrophysiological properties of AF over time. Methods: Atrial fibrillation (AF) was maintained for 3-4 weeks after pericardial electrode implantation in 12 goats. Within a single AF episode 10 consecutive minutes were mapped on the left atrial free wall using a 249-electrode array (2.25 mm inter-electrode spacing). AF cycle length, fractionation index (FI), lateral dissociation, conduction velocity, breakthroughs, and preferentiality of conduction (Pref) were assessed per electrode and AF property maps were constructed. The Pearson correlation coefficient (PCC) between the 10 AF-property maps was calculated to quantify the degree spatiotemporal stationarity of AF properties. Furthermore, the number of waves and presence of re-entrant circuits were analyzed in the first 60-s file. Comparing conduction patterns over time identified recurrent patterns of AF with the use of recurrence plots. Results: The averages of AF property maps were highly stable throughout the ten 60-s-recordings. Spatiotemporal stationarity was high for all 6 property maps, PCC ranged from 0.66 ± 0.11 for Pref to 0.98 ± 0.01 for FI. High stationarity was lost when AF was interrupted for about 1 h. However, the time delay between the recorded files within one episode did not affect PCC. Yet, multiple waves (7.7 ± 2.3) were present simultaneously within the recording area and during 9.2 ± 11% of the analyzed period a re-entrant circuit was observed. Recurrent patterns occurred rarely and were observed in only 3 out of 12 goats. Conclusions: During non-self-terminating AF in the goat, AF properties were stationary. Since this could not be attributed to stable recurrent conduction patterns during AF, it is suggested that AF properties are determined by anatomical and structural properties of the atria even when the conduction patterns are very variable.

Margarines and Fast-Food French Fries: Low Content of trans Fatty Acids.

The lipid fraction of margarines and fast food French fries, two types of foods traditionally high in trans fatty acids (TFA), is assessed. TFA data reported worldwide during the last 20 years have been gathered and show that some countries still report high TFA amounts in these products. The content of TFA was analysed in margarines (two store and four premium brands) and French-fries from fast-food restaurants (five chains). All samples were collected in Pamplona (Navarra, Spain). The margarines showed mean values of 0.68% and 0.43% (g TFA/100 g fat) for the store and premium brands, respectively. The French fries' values ranged from 0.49% to 0.89%. All samples were lower than the 2% set by some European countries as the maximum legal content of TFA in fats, and contained less than 0.5 g/serving, so they could also be considered "trans free products". This work confirmed that the presence of TFA is not significant in the two analysed products and contributes updated food composition tables, key tools for epidemiological and nutrition studies.